1) This continuation application develops from previous work on receptors for CCK, muscarinic, secretin/PHI/VIP, and GRP (gastrin-releasing peptide). Stimulus-secretion coupling in the exocrine pancreas will be tested: a) chemically, with covalent iodinated photoaffinity probes of receptors, and by 32p-ADP-ribosylation of the Mr 42,000 and Mr 50,000 subunits of the guanine nucleotide regulatory protein (N) (for identification and purification in solubilized systems) as well as by a possible phosphorylation of receptor components; b) by radiation inactivation, to determine the apparent size of receptors in situ under various conditions; c) functionally, by a quantitative evaluation of transient complexes of receptors with (N), adenylate cyclase and other effector systems, and resulting changes in metabolic activities. 2) To probe specifically the metabolic role of calmodulin, calmodulin-dependent proteins (including myosin light chain kinase and cyclic nucleotide phosphodiesterases) will be extracted by affinity chromatography, and fractionated by high performance gel permeation chromatography. Proteins phosphorylated insubcellular fractions, in the presence of the purified CaM-dependent kinase, will be compare to those proteins phosphorylated in isolated acini submitted to CCK, acetylcholine, GRP, and/or secretin-VIP. 3) Similar brain receptors will be investigated using methods comparable to those in 1-2. 4) These studies will be conducted on normal rats, guinea pigs, and mice, obese (fa/fa) Zucker rats, and obese-hyperglycemic (ob/ob) mice. 5) This project is mostly concerned with the neuroendocrine biochemistry of the pancreas. The comparison of the pharmacological activity of drugs acting as full and partial agonists or as antagonists with their ability to stabilize transient complexes in plasma membranes might be of great therapeutic interest in digestive and other diseases.